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American Journal of Physiology.... Feb 2020We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1...
We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
Topics: Amitriptyline; Aniline Compounds; Animals; Atherosclerosis; Benzylidene Compounds; Blood Glucose; Cytokines; Diet, High-Fat; Down-Regulation; Enzyme Inhibitors; Insulin Resistance; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Receptors, LDL; Sphingolipids; Sphingomyelin Phosphodiesterase
PubMed: 31821039
DOI: 10.1152/ajpendo.00181.2019 -
BMJ Clinical Evidence Jul 2009Chronic tension-type headache (CTTH) is a disorder that evolves from episodic tension-type headache, with daily or very frequent episodes of headache lasting minutes to... (Review)
Review
INTRODUCTION
Chronic tension-type headache (CTTH) is a disorder that evolves from episodic tension-type headache, with daily or very frequent episodes of headache lasting minutes to days. It affects 4.1% of the general population in the USA, and is more prevalent in women (up to 65% of cases).
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for chronic tension-type headache? What are the effects of non-drug treatments for chronic tension-type headache? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 50 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture; amitriptyline; analgesics; anticonvulsant drugs; benzodiazepines; botulinum toxin; chiropractic and osteopathic manipulations; cognitive behavioural therapy (CBT); Indian head massage; mirtazapine; relaxation and electromyographic biofeedback; selective serotonin reuptake inhibitor antidepressants (SSRIs); and tricyclic antidepressants (other than amitriptyline).
Topics: Amitriptyline; Headache; Humans; Manipulation, Osteopathic; Selective Serotonin Reuptake Inhibitors; Tension-Type Headache
PubMed: 21696647
DOI: No ID Found -
Basic Research in Cardiology Dec 2022Antidepressants have been reported to enhance stroke recovery independent of the presence of depressive symptoms. They have recently been proposed to exert their...
Antidepressants have been reported to enhance stroke recovery independent of the presence of depressive symptoms. They have recently been proposed to exert their mood-stabilizing actions by inhibition of acid sphingomyelinase (ASM), which catalyzes the hydrolysis of sphingomyelin to ceramide. Their restorative action post-ischemia/reperfusion (I/R) still had to be defined. Mice subjected to middle cerebral artery occlusion or cerebral microvascular endothelial cells exposed to oxygen-glucose deprivation were treated with vehicle or with the chemically and pharmacologically distinct antidepressants amitriptyline, fluoxetine or desipramine. Brain ASM activity significantly increased post-I/R, in line with elevated ceramide levels in microvessels. ASM inhibition by amitriptyline reduced ceramide levels, and increased microvascular length and branching point density in wildtype, but not sphingomyelinase phosphodiesterase-1 ([Smpd1]) (i.e., ASM-deficient) mice, as assessed by 3D light sheet microscopy. In cell culture, amitriptyline, fluoxetine, and desipramine increased endothelial tube formation, migration, VEGFR2 abundance and VEGF release. This effect was abolished by Smpd1 knockdown. Mechanistically, the promotion of angiogenesis by ASM inhibitors was mediated by small extracellular vesicles (sEVs) released from endothelial cells, which exhibited enhanced uptake in target cells. Proteomic analysis of sEVs revealed that ASM deactivation differentially regulated proteins implicated in protein export, focal adhesion, and extracellular matrix interaction. In vivo, the increased angiogenesis was accompanied by a profound brain remodeling response with increased blood-brain barrier integrity, reduced leukocyte infiltrates and increased neuronal survival. Antidepressive drugs potently boost angiogenesis in an ASM-dependent way. The release of sEVs by ASM inhibitors disclosed an elegant target, via which brain remodeling post-I/R can be amplified.
Topics: Amitriptyline; Animals; Antidepressive Agents; Brain; Ceramides; Desipramine; Endothelial Cells; Extracellular Vesicles; Fluoxetine; Ischemia; Mice; Proteomics
PubMed: 36038749
DOI: 10.1007/s00395-022-00950-7 -
The New England Journal of Medicine Jan 2017Which medication, if any, to use to prevent the headache of pediatric migraine has not been established. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Which medication, if any, to use to prevent the headache of pediatric migraine has not been established.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.
RESULTS
A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.
CONCLUSIONS
There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).
Topics: Adolescent; Amitriptyline; Anticonvulsants; Child; Double-Blind Method; Fatigue; Female; Fructose; Humans; Linear Models; Male; Migraine Disorders; Paresthesia; Placebos; Topiramate; Treatment Failure; Xerostomia
PubMed: 27788026
DOI: 10.1056/NEJMoa1610384 -
The Cochrane Database of Systematic... Jul 2015This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the effects of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the effects of amitriptyline for fibromyalgia are now dealt with in a separate review.Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage). It is recommended as a first line treatment in many guidelines. Neuropathic pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.
OBJECTIVES
To assess the analgesic efficacy of amitriptyline for relief of chronic neuropathic pain, and the adverse events associated with its use in clinical trials.
SEARCH METHODS
We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with two clinical trial registries, and the reference lists of retrieved papers, previous systematic reviews, and other reviews; we also used our own hand searched database for older studies.
SELECTION CRITERIA
We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in chronic neuropathic pain conditions.
DATA COLLECTION AND ANALYSIS
We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks' duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.
MAIN RESULTS
We included 15 studies from the earlier review and two new studies (17 studies, 1342 participants) in seven neuropathic pain conditions. Eight cross-over studies with 302 participants had a median of 36 participants, and nine parallel group studies with 1040 participants had a median of 84 participants. Study quality was modest, though most studies were at high risk of bias due to small size.There was no first-tier or second-tier evidence for amitriptyline in treating any neuropathic pain condition. Only third-tier evidence was available. For only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo (very low quality evidence).More participants experienced at least one adverse event; 55% of participants taking amitriptyline and 36% taking placebo. The risk ratio (RR) was 1.5 (95% confidence interval (CI) 1.3 to 1.8) and the number needed to treat for an additional harmful outcome was 5.2 (3.6 to 9.1) (low quality evidence). Serious adverse events were rare. Adverse event and all-cause withdrawals were not different, but were rarely reported (very low quality evidence).
AUTHORS' CONCLUSIONS
Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but only a minority of people will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.
Topics: Adult; Amitriptyline; Analgesics, Non-Narcotic; Antidepressive Agents, Tricyclic; Humans; Neuralgia; Randomized Controlled Trials as Topic
PubMed: 26146793
DOI: 10.1002/14651858.CD008242.pub3 -
International Journal of Molecular... Mar 2024Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent... (Review)
Review
Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.
Topics: Humans; Amitriptyline; Antidepressive Agents, Tricyclic; Drug Packaging; Environmental Pollutants; Environmental Restoration and Remediation
PubMed: 38612638
DOI: 10.3390/ijms25073822 -
Journal of Oral & Facial Pain and... 2022To evaluate the efficacy and safety of melatonin for migraine prophylaxis in adults. (Meta-Analysis)
Meta-Analysis
AIMS
To evaluate the efficacy and safety of melatonin for migraine prophylaxis in adults.
METHODS
After a comprehensive literature search in the MEDLINE, Cochrane Database, and International Clinical Trial Registry Platform databases, reviewers extracted data from three relevant articles. PRISMA guidelines were followed in the selection, analysis, and reporting of the findings. Quality assessment was performed using the Cochrane risk of bias assessment tool. A random-effects model was used to estimate the effect size, and meta-regression was performed for variables with a likely influence on effect size. Subgroup analysis was performed based on the comparison used in the included studies.
RESULTS
Melatonin therapy in migraine was associated with a significantly higher responder rate when compared to both placebo and standard therapy (OR = 1.84; 95% CI: 1.08 to 3.14; P = .03). The results of the meta-analyses indicated that melatonin can achieve a significant reduction in frequency of migraine attacks (MD = 1.00; 95% CI: 0.02 to 1.98; P = .04), migraine attack duration (MD = 5.02; 95% CI: 0. 91 to 9.13; P = .02), use of analgesics (MD = 1.43; 95% CI: 0.38 to 2.48; P = .008), and migraine severity (MD = 1.93; 95% CI: 1.23 to 2.63; P < .0001) over placebo, but had no significant effects in comparison to amitriptyline or valproate. There was no significant difference in the occurrence of common adverse drug reactions, such as drowsiness and fatigue, between the melatonin group and the comparison groups.
CONCLUSIONS
Melatonin showed a beneficial prophylactic role in migraine, with a better responder rate in comparison to placebo in reducing migraine severity, mean attack duration, mean attack frequency, and analgesic use, but did not show significant effects in comparison to amitriptyline or valproate.
Topics: Adult; Humans; Melatonin; Migraine Disorders; Valproic Acid; Amitriptyline; Analgesics
PubMed: 36445912
DOI: 10.11607/ofph.3211 -
Translational Psychiatry Feb 2021Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota-gut-brain axis. But the...
Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota-gut-brain axis. But the impact of antidepressants on gut microbiota function and composition remains poorly understood. Thus this study assessed the effect of serotonin reuptake inhibitor antidepressant fluoxetine (Flu) and tricyclic antidepressant amitriptyline (Ami) administration on gut microbiota composition, diversity, and species abundance, along with microbial function in a chronic unpredictable mild stress (CUMS)-induced depression rat model. Oral administration of Ami and Flu significantly altered the overall gut microbiota profile of CUMS-induced rats, as assessed using the permutational multivariate analysis of variance test. At the phylum level, 6-week of antidepressant treatment led to a decreased Firmicutes/Bacteroidetes ratio due to an enhanced Bacteroidetes and reduced Firmicutes relative abundance. Flu was more potent than Ami at altering the Firmicutes and Bacteroidetes levels in the CUMS rats. At the family level, both antidepressants significantly increased the abundance of Porphyromonadaceae. However, an increased Bacteroidaceae level was significantly associated with Ami, not Flu treatment. Furthermore, at the genus level, an increase in the relative abundance of Parabacteroides, Butyricimonas, and Alistipes was observed following Ami and Flu treatment. Subsequent metagenomics and bioinformatics analysis further indicated that Ami and Flu likely also modulated metabolic pathways, such as those involved in carbohydrate metabolism, membrane transport, and signal transduction. Additionally, both antidepressants affected antibiotic resistome, such as for aminoglycoside (aph3iiiA), multidrug (mdtK, mdtP, mdtH, mdtG, acrA), and tetracycline (tetM) resistance in CUMS rats. These data clearly illustrated the direct impact of oral administration of Flu and Ami on the gut microbiome, thus set up the foundation to reveal more insights on the therapeutic function of the antidepressants and their overall contribution to host health.
Topics: Amitriptyline; Animals; Antidepressive Agents; Fluoxetine; Gastrointestinal Microbiome; Rats; Stress, Psychological
PubMed: 33602895
DOI: 10.1038/s41398-021-01254-5 -
Spinal Cord Series and Cases Jul 2022Systematic review.
STUDY DESIGN
Systematic review.
OBJECTIVES
This systematic review evaluates all randomized clinical trials (RCTs) conducted on assessing the efficacy and safety of pharmacologic therapies for the treatment of Spinal Cord Injury (SCI)-associated pain.
METHODS
The PubMed/Medline, EMBASE, and Cochrane library online databases were searched from 1946 to May 2019 using specific search terms for SCI, pain, and RCTs meeting predetermined inclusion criteria. The efficacy outcome of interest was pain reduction, discontinuations, and adverse events (AEs).
RESULTS
Of 2746 records identified through database searching, 703 duplicates were deleted. 1814 were excluded, the full text of the remaining 230 articles was reviewed, and finally, 28 papers were selected for drafting. The most studied medications were pregabalin, gabapentin, amitriptyline, and ketamine. Pregabalin, gabapentin, and amitriptyline reduced VAS by more than 30%, and ketamine reduced VAS by 40%. Oxcarbazepine, lamotrigine, alfentanil, tramadol, and morphine added to clonidine, baclofen, and botulinum toxin type A (BTA) significantly reduced pain compared with placebo. On the other hand, valproate, levetiracetam, trazodone, and duloxetine did not significantly alleviate SCI-associated pain compared to placebo. The risks of AEs and discontinuations in anticonvulsants were the least, while it was highest in analgesics.
CONCLUSIONS
Studies of SCI-associated pain were few, small, heterogenic in measures and values, and did not allow quantitative comparisons of efficacy. However, available data suggested pregabalin and gabapentin led to a more marked reduction in SCI-associated pain with fewer AEs. Additional clinical studies are needed to assess the effect of established and novel management options.
Topics: Amitriptyline; Anticonvulsants; Gabapentin; Humans; Ketamine; Pain; Pregabalin; Spinal Cord Injuries
PubMed: 35788127
DOI: 10.1038/s41394-022-00529-3 -
International Journal of Molecular... Dec 2022The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and...
The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li+, which suppresses the sodium−calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li+]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li+]s of 0.5−1 mM cause an increase in ATL and DES IC50s of ~10 folds and ~4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li+. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li+. This Ca2+-dependent interplay between Li+, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li+]s may weaken ATL and DES effects during combined therapy. The data suggest that Li+, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug−drug or ion−drug interaction when these medicines are used together therapeutically.
Topics: Rats; Animals; Antidepressive Agents, Tricyclic; Amitriptyline; Receptors, N-Methyl-D-Aspartate; Lithium; Calcium; Desipramine; Calcium, Dietary
PubMed: 36555818
DOI: 10.3390/ijms232416177